High Density Lipoproteins and Diabetes - Review - MDPI
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
cells
Review
High Density Lipoproteins and Diabetes
Blake J. Cochran , Kwok-Leung Ong , Bikash Manandhar and Kerry-Anne Rye *
Lipid Research Group, School of Medical Sciences, Faculty of Medicine, University of New South Wales Sydney,
Sydney, NSW 2052, Australia; b.cochran@unsw.edu.au (B.J.C.); kwokleung.ong@unsw.edu.au (K.-L.O.);
b.manandhar@student.unsw.edu (B.M.)
* Correspondence: k.rye@unsw.edu.au; Tel.: +61-2-9385-1219; Fax: +61-2-9385-1389
Abstract: Epidemiological studies have established that a high plasma high density lipoprotein
cholesterol (HDL-C) level is associated with reduced cardiovascular risk. However, recent ran-
domised clinical trials of interventions that increase HDL-C levels have failed to establish a causal
basis for this relationship. This has led to a shift in HDL research efforts towards developing strate-
gies that improve the cardioprotective functions of HDLs, rather than simply increasing HDL-C
levels. These efforts are also leading to the discovery of novel HDL functions that are unrelated
to cardiovascular disease. One of the most recently identified functions of HDLs is their potent
antidiabetic properties. The antidiabetic functions of HDLs, and recent key advances in this area
are the subject of this review. Given that all forms of diabetes are increasing at an alarming rate
globally, there is a clear unmet need to identify and develop new approaches that will complement
existing therapies and reduce disease progression as well as reverse established disease. Exploration
of a potential role for HDLs and their constituent lipids and apolipoproteins in this area is clearly
warranted. This review highlights focus areas that have yet to be investigated and potential strategies
for exploiting the antidiabetic functions of HDLs.
Citation: Cochran, B.J.; Ong, K.-L.;
Keywords: HDL; apoA-I; diabetes; β-cells; skeletal muscle
Manandhar, B.; Rye, K.-A. High
Density Lipoproteins and Diabetes.
Cells 2021, 10, 850. https://doi.org/
10.3390/cells10040850 1. Introduction
Epidemiological studies have established unequivocally that a high plasma HDL
Academic Editor: Alberico cholesterol (HDL-C) level is associated with a reduced risk of having a cardiovascular
L. Catapano event [1,2]. The strength of this relationship led to the “HDL hypothesis” which posits
that the inverse association of HDL-C levels with cardiovascular risk is potentially causal,
Received: 31 January 2021
such that increasing HDL-C levels will reduce cardiovascular events [3]. The HDL hy-
Accepted: 1 April 2021
pothesis was initially supported by preclinical studies in which increasing HDL-C levels
Published: 9 April 2021
chronically in rabbits using a cholesteryl ester transfer protein (CETP) inhibitor [4] and in
mice using niacin [5], or acutely by infusing synthetic, reconstituted HDL (rHDL) prepara-
Publisher’s Note: MDPI stays neutral
tions reduced atherosclerosis [6].
with regard to jurisdictional claims in
However, the promise of these preclinical studies was dispelled when the “HDL
published maps and institutional affil-
hypothesis” was tested in large, randomised clinical trials of niacin and CETP inhibitors
iations.
in which, with one exception, cardiovascular events were not decreased in the face of
significantly increased HDL-C levels [7–13]. Of all of the randomised clinical trials of
HDL-raising agents reported so far, the CETP inhibitor anacetrapib is the only one that that
has significantly reduced cardiovascular events [14]. However, the positive outcome in that
Copyright: © 2021 by the authors.
trial was largely due to a reduction in low density lipoprotein cholesterol (LDL-C) levels,
Licensee MDPI, Basel, Switzerland.
not the increase in HDL-C levels. Dalcetrapib, a CETP inhibitor that modestly increases
This article is an open access article
HDL-C levels and does not lower LDL-C levels [13], was found to potentially improve
distributed under the terms and
cardiovascular outcomes in patients carrying the AA polymorphism of the adenylate
conditions of the Creative Commons
Attribution (CC BY) license (https://
cyclase type 9 (ADCY9) gene [15], although this benefit could not be replicated in patients
creativecommons.org/licenses/by/
that were treated with the CETP inhibitor, evacetrapib [16]. Nevertheless, use of dalcetrapib
4.0/). is currently under investigation in acute coronary syndrome patients with the AA ADCY9
Cells 2021, 10, 850. https://doi.org/10.3390/cells10040850 https://www.mdpi.com/journal/cellsCells 2021, 10, 850 2 of 16
genotype in a placebo-controlled, randomised, double-blind, parallel group, multicentre
Phase III study [17].
Additional evidence negating the “HDL hypothesis” has emerged from Mendelian
Randomisation studies, where genetically driven variations in HDL-C levels were found
not to be associated with reduced cardiovascular risk [18]. However, the results of such
studies should be interpreted with caution given that Mendelian Randomisation reports
on linear relationships, whereas the association of HDL-C levels with cardiovascular risk is
U- or J-shaped, with very low and very high HDL-C levels reported to be associated with
increased mortality [19,20].
These disappointing outcomes have led to a paradigm shift in the focus of the HDL
research community towards identifying other functions of HDLs and the possibility of tar-
geting the treatment of disorders that are unrelated to cardiovascular disease. This has led
to extensive investigation into a potential role for HDLs in the treatment of inflammatory
diseases and diseases where oxidative stress is a key component, such as arthritis [21], can-
cer [20] and inflammatory bowel disease [22]. One of the most unexpected and important
beneficial functions of HDLs to have emerged in recent years is the discovery that HDLs
and some of their constituent apolipoproteins have potent antidiabetic properties [22–28].
Diabetes presents in two main forms in humans. Type 1 diabetes (T1D), an autoim-
mune disorder in which insulin producing β-cells in the pancreas are selectively destroyed
by autoreactive, proinflammatory T-cells. T1D affects approximately 10% of all patients
with the disease [29,30]. T2D, by contrast, is the predominant form of the disease and
affects ~90% of all patients [31,32]. T2D is driven by insulin resistance, which decreases
the uptake of glucose from blood into peripheral tissues. β-cells compensate for insulin
resistance and maintain blood glucose homeostasis by increasing insulin secretion [33,34].
However, prolonged β-cell compensation eventually causes β-cell death, and results in
subjects with prediabetes that have impaired fasting glucose and/or impaired glucose
tolerance transitioning to complete loss of β-cell function, persistently high blood glucose
levels and full blown T2D [35].
In vitro and preclinical studies in animal models of diabetes, together with mounting
epidemiological evidence, have generated considerable interest in the development of HDL-
targeted therapies as an innovative treatment option for both T1D and T2D. As a diagnosis of
diabetes is also associated with increased cardiovascular risk, it is noteworthy that therapies
that increase HDL levels and additionally decrease diabetes progression and/or reverse
established disease will have the added benefit of reducing cardiovascular risk.
2. Epidemiology of the Antidiabetic Functions of HDLs
2.1. Overview
A low HDL-C level has been established as a robust risk factor of diabetes in several
epidemiological studies [36,37]. It has been estimated that T2D risk over a 7-year follow up
period is about 4% lower per 1 mg/dL increase in HDL-C in the Framingham Offspring
Study [36]. In a prospective study of 6820 nondiabetic participants from the Prevention of
Renal and Vascular End-Stage Disease (PREVEND) cohort, a higher HDL-C level, a higher
HDL-C/apolipoprotein A-I (apoA-I) ratio and a higher HDL-C/apolipoprotein A-II (apoA-
II) ratio were all independently associated with reduction in the risk of incident T2D [38].
Conversely, a recent study of over 5 million nondiabetic adults from the Korean National
Health Insurance System cohort reported that a low HDL-C level was associated with a
higher risk of developing diabetes over a median follow-up period of 5.1 years, and that this
was exacerbated in patients with highly variable HDL-C levels [39]. In another large Korean
study of 27,988 subjects with impaired fasting glucose a higher HDL-C was, by contrast,
not significantly associated with lower risk of incident T2D over 2.8 years [40]. However,
in that study a higher HDL-C/apoA-I ratio was significantly associated with a lower risk
of incident T2D [40]. This finding was subsequently validated and extended in a study
of Caucasian patients with T2D in whom a higher HDL-C/apoA-I ratio was associated
with improved β-cell function and a reduced risk of macrovascular and microangiopathicCells 2021, 10, 850 3 of 16
complications [41]. As HDL particle size is directly proportional to the HDL-C/apoA-I ratio,
these results suggest that there is a potential specificity associated with the antidiabetic
properties of HDLs, with large particles having superior antidiabetic functions compared
to small HDLs. This possibility is clearly worthy of further investigation.
2.2. Epidemiological Insights into HDL Subtypes in Diabetes
The HDLs in human plasma comprise several subpopulations of particles that are
diverse in terms of size, density, surface charge and composition [42]. Emerging evidence
suggests that these HDL subtypes may also be functionally distinct, at least in a cardiovascu-
lar disease setting [43,44]. Given that the three most abundant apolipoprotein constituents
of HDLs, apoA-I, apoA-II and apoA-IV, all have antidiabetic functions, but that they are not
uniformly distributed between all HDL subtypes, it is highly likely that this may also be
the case for diabetes [23,25,45,46]. Although it has yet to be investigated systematically, ad-
ditional evidence that HDL subtypes may be functionally distinct comes from the fact that
patients with T1D tend to have HDLs that are larger than those found in healthy people,
while small HDLs predominate in people with T2D [47–49]. The functional implications of
this difference in HDL size has not been explored systematically, but there is some evidence
to suggest that the HDLs in T1D and T2D are, indeed, functionally diverse [50].
Type 1 Diabetes
Most patients with T1D have a normal or significantly increased HDL-C level, a re-
duced total number of HDL particles, and an increased number of large HDL particles
relative to that of well-matched, healthy control subjects [48,51]. The functional implica-
tions of these differences have been focussed so far on the cholesterol efflux capacity of
plasma from these patients, which is consistently enhanced relative to that of nondiabetic
controls [48]. While this improvement in HDL function is potentially beneficial, the mecha-
nistic basis of the finding requires further validation because a significant proportion of
the increased cholesterol efflux in these subjects is dependent on the ATP binding cassette
transporter, ABCA1, which effluxes cholesterol to lipid-free or lipid-poor apoA-I, not to
the large HDLs that predominate in these individuals [48]. Collectively, these observations
suggest that the large HDL particles in patients with T1D may not be fully functional.
It also raises the possibility that HDLs from patients with T1D may have an increased
susceptibility to remodelling by plasma factors such as CETP and phospholipid transfer
protein, both of which generate lipid-free or lipid-poor apoA-I.
T1D also has a significant impact on the HDL proteome. This area is yet to be explored
in detail, but a recent cross-sectional, case–control study of isolated HDLs from young
patients with T1D identified significant differences in the protein cargo of HDLs in affected
subjects relative to healthy controls [52]. Some of these changes, such as the presence of
proteins that are linked to complement activation, appear to be regulated by the extent of
glycaemic control, but how this impacts on HDL subpopulation distribution and affects
HDL function is not known [52]. It is noteworthy that the cholesterol efflux capacity of
the HDLs from the subjects with T1D in that study was comparable to that of healthy
controls, an observation that is at odds with the increased efflux in T1D patients that has
been reported by Ahmed et al. [48]. The reason for this discrepancy is not clear, but it may
reflect differences in average patient age (17 versus 37 years), lifestyle factors (smoking,
alcohol intake), and uptake of lipid lowering and increased post translational modifications
of HDL apolipoproteins in the older cohort with longer duration diabetes.
Poor glycaemic control in patients with T1D seems to exacerbate changes in HDL sub-
type distribution. In a small cross-sectional study of 52 adolescents with T1D, those with
poor glycaemic control had a lower level of large HDL2 particles than those with reasonable
glycaemic control, despite having similar HDL-C levels. This difference in HDL subtype
distribution suggests that poor glycaemic control reduces the number of HDL particles,
but does not impact on HDL function, with cholesterol efflux from hepatoma cells to
serum and isolated HDLs being comparable for all of the subjects [53]. In a recent study
of T1D patients, by contrast, elevated medium-sized HDL particles and a higher levelCells 2021, 10, 850 4 of 16
of HDL-associated paraoxonase (PON) 1 were associated with fewer vascular complica-
tions [47]. This result provides further evidence that HDL subclasses in patients with T1D
are functionally distinct.
It is important to note that interpretation of all of the above studies is significantly
limited by their cross-sectional design. This raises the possibility that the conclusions may
be attributable to reverse causality and begs the question of whether any of the observed
associations have a causal basis.
Type 2 Diabetes
As ~90% of all patients with diabetes have T2D, there is much more information on the
epidemiology of the antidiabetic functions of HDLs in this group than in patients with T1D.
The decrease in HDL size in insulin-resistant T2D patients has been reported to correlate
with a decrease in the number of large HDL particles and an increase in the number of
small HDL particles for a given HDL-C level, indicating that T2D may increase the number
of HDL particles [54].
In a large, prospective 13-year study of over 26,000 participants where HDL subclasses
were evaluated by NMR spectroscopy in healthy women that subsequently developed type
2 diabetes, small HDLs were positively associated with disease development, while large
HDLs were inversely associated with disease development [55]. This result is supported
by a more recent, cross-sectional study of over 8000 participants in which the homeostasis
model assessment of insulin resistance (HOMA-IR) was found to be inversely associated
with HDL2 cholesterol levels and positively associated with HDL3 cholesterol levels [56].
Similar results were obtained from a smaller, 5-year prospective study in which HDL2 -C
levels were inversely associated with the risk of incident type 2 diabetes, and in another
study in which the inclusion of a low plasma apoA-I level improved the power of the
established T2D risk prediction models [56,57].
Evidence that insulin resistance may drive HDL subclass distribution towards smaller
particles in patients with type 2 diabetes has also been obtained from a small cohort of
patients in whom insulin sensitivity was evaluated by hyperinsulinemic clamp, and another
prospective study in which HOMA-IR and small HDLs were positively associated with
incident diabetes over 7.7-years [54,58]. Whether the relationship between insulin resistance
and small HDLs is causal remains to be seen, but it could be postulated that some of the
proteins that are selectively transported by small HDL particles inactivate insulin signalling
pathways in skeletal muscle and adipose tissue.
A small, prospective study of Japanese Americans, in which a high total HDL-C level
was associated with a lower future risk of T2D, further suggested that HDL subtypes
may be differentially associated with insulin resistance and T2D risk [59]. Although this
association was apparent in patients with a high HDL2 -C level, but not a high HDL3 -C level,
it was no longer significant after adjusting for visceral adipose tissue area. This suggested
that the association may have been mediated by the visceral fat depot, a well-known risk
factor for insulin resistance and T2D [60]. However, there is likely to be some validity in
this association as an inverse association of a high HDL2 -C level with T2D risk has also
been reported in a much larger, cross-sectional, community-based cohort of 8365 subjects
in which a high HDL2 -C level was associated with reduced insulin resistance, while a high
HDL3 -C level was associated with more severe insulin resistance [56].
The issue of whether or not there is a causal basis for any of these relationships
between HDL sand T2D was addressed directly in a Mendelian Randomisation study of
over 47,000 participants in the Copenhagen City Heart Study and the Copenhagen General
Population Study [61]. The results of that study did not find any evidence of an association
of genetic variants with low HDL-C levels and T2D risk [61]. However, that study did not
assess the relationship of HDL subtypes, or any aspects of HDL function with T2D risk.
The first direct evidence that the antidiabetic functions of HDLs is causal in hu-
mans was obtained from a double-blind, placebo-controlled crossover study of 13 T2D
patients, in which plasma HDL levels were transiently increased by the administration of
a single intravenous infusion of rHDLs [62]. These patients all sustained a reduction inCells 2021, 10, 850 5 of 16
plasma glucose and an increase in plasma insulin levels, and an overall improvement in
glycaemic control [62].
The antidiabetic functions of HDLs are further supported by data from large-scale ran-
domised clinical trials of CETP inhibitors, which chronically increase plasma HDL-C and
apoA-I levels. In the Investigation of Lipid Level Management to Understand its Impact in
Atherosclerotic Events (ILLUMINATE) trial, treatment with the CETP inhibitor, torcetrapib,
improved glycaemic control in statin-treated patients with T2D [12]. A similar result was
obtained in the Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibi-
tion with Evacetrapib in Patients with at High Risk for Vascular Outcomes (ACCELERATE)
trial, where glycaemic control was found to be improved in T2D patients [63]. Finally,
treatment with two other CETP inhibitors, anacetrapib, and dalcetrapib was also found
to be associated with a reduced risk of new-onset diabetes in large, randomised clinical
outcome trials [14,64]. Insights into the effects of HDL-raising agents on glycaemic control
from randomised clinical trials are summarised in Table 1. Whether these beneficial effects
are a direct consequence of the increased level of HDLs, or whether they are due to the
increased HDL levels counteracting the negative effects of statin treatment in these patients
is not known [65].
Table 1. Summary of randomised clinical trials demonstrating the antidiabetic functions of HDLs in humans.
Intervention n Impact on HDL-C Impact on T2D Reference
Reconstituted HDL
Infusion
Reduced plasma glucose
rHDL 13 ↑33 ± 4.3% Ref [62]: Drew et al., 2009
Increased plasma insulin
CETP inhibition
Evacetrapib
8236 ↑131.9 ± 56% Decreased HbA1c Ref [63]: Menon et al., 2020
(ACCELERATE)
Anacetrapib Reduced risk of new-onset Ref [14]: HPS TIMI REVEAL
30,449 ↑152.8 ± 1.6%
(REVEAL) diabetes Collaborative Group
Decreased glucose
Torcetrapib Decreased insulin
15,067 ↑72.1 ± 34.7% Ref [12]: Barter et al., 2007
(ILLUMINATE) Decreased insulin resistance
Decreased HbA1c
Reduced risk of new-onset
Dalcetrapib
15,871 ↑33.9 ± 2.8% diabetes in acute coronary Ref [13]: Schwartz et al., 2020
(dal-OUTCOMES)
syndrome patients
3. Apolipoproteins and the Antidiabetic Functions of High Density Lipoproteins
Early in vitro and preclinical studies have indicated that the three most abundant
HDL apolipoproteins, apoA-I, apoA-II and apoA-IV all have antidiabetic properties [23,25].
Conversely, the small, exchangeable apolipoprotein, apoC-III, that is associated with HDLs
in normal, healthy people has a potentially adverse effect in patients with diabetes, with
lower apoC-III levels being associated with delayed onset of disease [66]. ApoC-III has
also been reported to promote β-cell death [67].
3.1. Apolipoprotein A-I and Apolipoprotein A-II
The first direct evidence that HDLs and apoA-I have potential therapeutic value in
humans with diabetes came from the aforementioned study in which a single infusion
of rHDLs prepared with apoA-I and soybean phosphatidylcholine improved glycaemic
control in patients with T2D [62]. The basis of the improved glycaemic control in these
individuals was attributed to increased secretion of insulin from β-cells and enhanced
glucose uptake into skeletal muscle [62]. This result is consistent with what has been
reported for apoA-I knockout mice that have impaired glucose tolerance, in mice thatCells 2021, 10, 850 6 of 16
overexpress human apoA-I and have improved glucose tolerance, and in in vitro studies of
cultured skeletal muscle cells where incubation with lipid-free apoA-I has been reported to
increase glucose uptake in an insulin-dependent and -independent manner by increasing
glycolysis and mitochondrial respiration [27,28,68–70]. Some of these studies are particu-
larly important because they suggest that apoA-I- and HDL-based therapies may improve
glycaemic control in patients with T2D that have complete loss of β-cell function and are
refractory to many of the currently available antidiabetic therapies [28,71].
Other in vitro studies have revealed that apoA-I and apoA-II in both lipid-free and
lipid-associated forms increase insulin synthesis and glucose stimulated insulin secretion
(GSIS) in the MIN6 and Ins-1E pancreatic insulinoma β-cell lines [22,23]. The mechanis-
tic basis of these observations involves the activation of a G-protein-cAMP-PKA-FoxO1
pathway, is dependent on the internalization of lipid-free apoA-I into the β-cells, and is
associated with the increased expression of the β-cell survival gene, pancreatic and duo-
denal homeobox 1 (Pdx1) [22,72]. The ability of lipid-free apoA-I and apoA-II to increase
Pdx1 gene expression raises the possibility that these apolipoproteins may conserve β-cell
function and reduce the adverse effects of activated T-cells in T1D [73,74]. Additionally,
all HDL subclasses have been shown to be equally effective at increasing insulin secretion
in MIN6 cells [75].
HDLs also protect β-cells from the apoptosis that occurs when blood glucose and
free fatty acid levels are increased by endoplasmic reticulum (ER) stress-dependent and
-independent mechanisms [76,77]. The ability of HDLs and lipid-free apoA-I to inhibit
apoptosis in β-cells has additionally been attributed to reduced expression of the proin-
flammatory cytokine, interleukin (IL)-1β [78]. While apoA-II is as effective as apoA-I at
improving β-cell function in both lipid-free and lipid-associated forms [23], it is not known
if it operates through the same mechanisms.
Evidence that the antidiabetic functions of apoA-I and apoA-II translate into improved
glycaemic control in vivo is mounting. For example, lipid-free apoA-I treatment increases
glucose-stimulated insulin secretion (GSIS) in C57BL6 mice with diet-induced obesity,
and in isolated islets from mice with elevated islet cholesterol levels and impaired insulin
secretion due to the conditional deletion of the ATP binding cassette transporters, ABCA1
and ABCG1, which export cholesterol from β-cells to lipid-free/lipid-poor apoA-I and
HDLs, respectively [24,26,27,79]. However, the precise mechanism by which apoA-I im-
proves β-cell function in this animal model has yet to be elucidated. What we do know is
that the observed benefit is not related to the restoration of β-cell cholesterol homeostasis
in the case of mice with conditional deletion of ABCA1 and ABCG1 in β-cells [24]. Nor is it
related to improved glucose metabolism or to the inhibition of inflammation [24].
ApoA-I also reduces insulin resistance in validated mouse models of T2D. Treatment
of insulin-resistant db/db mice with lipid-free apoA-I increases glucose uptake by skeletal
muscle 1.8-fold [80]. Similar results have also been obtained following lipid-free apoA-I
treatment of mice with diet-induced obesity and in rats with pregnancy-induced insulin
resistance [26,27,81,82]. The ability of apoA-I to reduce insulin resistance in pregnancy were
not, however, confirmed in a recent small, retrospective cross-sectional study of women
with gestational diabetes, where serum apoA-I levels were found not to be associated
with insulin sensitivity [83]. This discrepancy between the animal and the human studies
may be because the apoA-I levels in the animal studies were increased with infusions of
unmodified, lipid-free apoA-I, whereas the analyses in the human study were based entirely
on differences in endogenous plasma levels of apoA-I that is likely to have undergone
post-translational modification and varying amounts of inactivation depending on the
duration of the gestational diabetes [50,83]. Whether the infusion of apoA-I that has not
been modified in any way and is therefore fully functional into women with gestational
diabetes would reduce pregnancy-induced insulin resistance is not known but is a question
that is undoubtedly of interest. The evidence that this may be potentially advantageous
comes from the increased uptake of glucose by skeletal muscle that has been reported in
patients with T2D in whom circulating HDL levels were increased with a single infusionCells 2021, 10, 850 7 of 16
of rHDLs [62]. Whether apoA-II also improves insulin sensitivity by increasing glucose
uptake into skeletal muscle is not known. This is a question of considerable interest given
that there are few known functions of this highly conserved apolipoprotein.
Lipid free apoA-I treatment has also been shown to increase glucose uptake into the
heart in mice [27,81]. These findings have recently been extended in a further mouse study
which showed that the ability of apoA-I-containing rHDLs to increase glucose uptake into
the heart during myocardial ischemia is associated with reduced cardiac damage [84].
While most investigations into the antidiabetic functions of HDLs and apoA-I have
focussed on improving β-cell function and/or insulin sensitivity, there is increasing interest
in their effects on α-cells in pancreatic islets. α-cells, the second most abundant cell type
in the endocrine pancreas after β-cells, secrete glucagon, which increases blood glucose
levels [85]. It has recently been reported that plasma HDL-C levels are inversely associated
with fasting glucagon levels in a normal, healthy population [86]. The evidence that this
relationship may be causal has been obtained by showing that treating hypoglycaemic
mice with isolated HDLs and lipid-free apoA-I reduces glucagon secretion by inhibiting
the activation of the PI3K/Akt/FoxO1 signalling pathway in a scavenger receptor B1
(SR-B1)-dependent manner [86].
3.2. Apolipoprotein A-IV
ApoA-IV, the third most abundant HDL apolipoprotein after apoA-I and apoA-II,
also has antidiabetic functions. This observation was first reported in a landmark study
where high-fat fed apoA-IV knockout mice were found to be glucose intolerant, and that
glycaemic control in these animals was restored by the administration of recombinant
mouse apoA-IV [25]. The benefit of apoA-IV in that study was attributed to improved β-
cell function, as evidenced by ex vivo apoA-IV treatment of the isolated islets from apoA-IV
knockout mice increasing GSIS [25]. While treatment of apoA-IV knockout mice with apoA-
IV did not increase glucose disposal in skeletal muscle in the initial study [25], a more recent
study has established that this apolipoprotein does improve insulin sensitivity in wild-type
C57BL6 mice by increasing glucose uptake into adipocytes and cardiac muscle [25,87].
3.3. Apolipoprotein C-III
ApoC-II is a small, exchangeable apolipoprotein that associates with HDLs in normal,
healthy individuals, but is predominantly incorporated into triglyceride-rich lipoproteins
in subjects with high plasma triglyceride levels [88]. As a high plasma triglyceride level is
a hallmark feature of T2D, but not T1D, it follows that the distribution of apoC-III across
plasma lipoproteins will vary according to diabetes type [89].
Epidemiological studies have established that plasma apoC-III levels are positively
associated with diabetes, and that Apoc3/APOC3 gene transcription increases in rat and
human hepatocytes under high glucose conditions and is inhibited by insulin [90–94].
Indirect evidence that apoC-III may be causally related to the development of diabetes was
obtained from a small randomised, double-blind, placebo-controlled clinical trial of patients
with T2D in which treatment with an apoC-III antisense oligonucleotide that reduced
plasma apoC-III levels by 88% increased HDL-C levels and improved insulin sensitivity [95].
Treatment with an apoC-III antisense oligonucleotide also reduces circulating apoC-III
levels, delays disease onset in a rat model of T1D and improves glucose tolerance in
insulin-resistant ob/ob mice [66,96].
Mechanistically, the adverse effects of apoC-III in diabetes appear to be related to
aberrant Ca2+ handling in β-cells, which increases intracellular Ca2+ levels [67,96]. Stud-
ies in the Ins-1E cell line have indicated that apoC-III causes islet inflammation and β-cell
apoptosis by activating mitogen-activated protein kinase (MAPK) and the extracellular
signal-regulated protein kinase ERK1/2 [97]. However, the ability of apoC-III to promote
β-cell apoptosis is controversial as it has also been reported to inhibit apoptosis in iso-
lated islets by activating PI3K/Akt signalling, with no effect on MAPK or ERK1/2 [98].
The reasons for these discrepant results are not clear, but may be related to the fact thatCells 2021, 10, 850 8 of 16
the isolated islets in the latter study of Storling et al. were preconditioned with apoC-III
prior to stimulation with proinflammatory cytokines, which was not the case in the other
investigations [67,96,97]. It is also possible that these discrepant results reflect fundamental
differences in the processes that are mediated by apoC-III in Ins-1E cells and primary islets.
Irrespective of whether apoC-III is pro- or antiapoptotic, the currently available in-
sights indicate that this apolipoprotein has the potential to impact adversely on glycaemic
control in patients with T1D and T2D by reducing β-cell function. Whether apoC-III also
adversely impacts on insulin sensitivity has not been investigated directly. This is clearly an
area that warrants further investigation at the preclinical stage as well as in human studies.
4. Diabetes and the Regulation of High Density Lipoprotein Function
The lipid and apolipoprotein constituents of HDLs are both susceptible to modifica-
tions that have the potential to impact adversely on the antidiabetic and cardioprotective
functions of HDLs. Although this is an area of considerable importance, it has not been
investigated systematically, with many key questions remaining unanswered. As a result,
little progress has been made in recent years in identifying therapeutic targets that may
inhibit these modifications in patients with diabetes. This is clearly an area worthy of
investigation going forward.
4.1. Nonenzymatic Glycation
The nonenzymatic glycation of apoA-I that occurs as a consequence of spontaneous
interaction with reactive α-oxoaldehydes generates a diverse array of advanced glyca-
tion end-products (AGEs) including Nε-(carboxyethyl) lysine, Nε-(carboxymethyl) lysine
and Nω-(carboxymethyl) arginine and is an extensively studied HDL modifications in
diabetes [99–101]. AGE formation is particularly prevalent in patients with poor gly-
caemic control [50].
Nonenzymatic glycation of apoA-I impairs several of the cardioprotective func-
tions of HDLs, including their ability to accept the excess cholesterol that effluxes from
macrophages in the artery wall, the process that drives the first step in the reverse choles-
terol transport pathway [71,102–106]. However, impaired cholesterol efflux has not been
reported in all patients with diabetes. For example, in a cross-sectional study of 552 subjects
that included 288 controls, 126 subjects with impaired glucose tolerance and 138 subjects
with T2D, cholesterol efflux was comparable across all three groups of subjects [107].
While the cross-sectional design of that study and the potential for reverse causality may
explain this discrepant result, it also raises the possibility that there may be a threshold
level of nonenzymatic glycation of apoA-I and other apolipoproteins, below which the
HDL function is not compromised.
It should, however, be noted that only selected reactive α-oxoaldehyde-mediated
modifications to apoA-I reduce cholesterol efflux. For example, methylglyoxal, one of
the most abundant α-oxoaldehydes in diabetic plasma nonenzymatically glycates apoA-I
extensively but does not affect the capacity of apoA-I to efflux cholesterol from fibroblasts
or macrophages (Figure 1) [108]. Glycoaldehyde and glyoxal, by contrast, both nonenzy-
matically glycate apoA-I and have been reported to markedly impair its ability to promote
cholesterol efflux from macrophages by destabilising ABCA1 (Figure 1) [108]. The re-
sult for glycoaldehyde was, by contrast, not confirmed in a more recent study using
macrophages [99]. The reason for this discrepant result is not clear but may be related to
the different glycoaldehyde concentrations that were used in the studies. CYP7A1 and
RAGE also reduce the ability of ABCA1 to efflux cholesterol from macrophages to apoA-I
in patients with T2D [109,110]. Nonenzymatic glycation additionally prevents apoA-I from
inhibiting one of the initiating events in atherosclerotic lesion development: the recruitment
of human monocytes to the endothelial surface [102]. rHDLs that contain nonenzymatically
glycated apoA-I also have a reduced capacity to increase glucose uptake into cultured
skeletal muscle cells and improve insulin secretion from Ins-1E cells [71].Cells 2021, 10, 850 9 of 16
a-oxoaldehyde Cholesterol efflux Glucose disposal Glucose stimulated
modification insulin secretion
Ref 108: Passarelli et al. 2005
Ref 99: Brown 2013
Ref 71: Domingo-Espin et al. 2018 Ref 71: Domingo-Espin et al. 2018
Ref 71: Domingo-Espin et al. 2018
Ref 102: Hoang et al. 2007
Methylglyoxal
Ref 108: Passarelli 2005
Ref 99: Brown 2013 Ref 71: Domingo-Espin et al. 2018 Ref 71: Domingo-Espin et al. 2018
Glycoaldehyde Ref 71: Domingo-Espin 2018
Ref 108: Passarelli 2005
Glyoxal
Figure 1. Nonenzymatic glycation of apoA-I impairs HDL function.
ApoA-I that has been nonenzymatically glycated glycated by the reactive α-oxoaldehydes,
glycoaldehyde and glyoxal, has an impaired ability accept cholesterol from cells. Nonenzy-
matic glycation of apoA-I with the reactive α-oxoaldehyde, methylglyoxal, has variable
effects on cholesterol efflux. Nonenzymatic glycation impairs the ability of apoA-I to
mediate glucose disposal in skeletal muscle and increase insulin secretion in response to
glucose in β-cells.
While mechanistic insights into the reduced efflux of cholesterol from mouse J774
macrophages to HDLs under conditions that favour nonenzymatic glycation have focussed
on apoA-I [71], extensive post-translational modification to other components of the HDL
proteome, including deamidation and carbonylation and impaired lipid binding capacity
may also contribute significantly to the loss of HDL function in diabetes [71,99,111,112].
Importantly, the adverse effects of nonenzymatic glycation on some of the cardioprotec-
tive functions of apoA-I, including the efflux of cholesterol from THP-1 macrophages, can be
reversed by inhibiting glycation with aminoguanidine, and by reducing AGE levels with
the cross-link breaker alagebrium chloride [102]. Alagebrium as well as the insulin sensitiser
metformin, and pyridoxamine which inhibits AGE formation and scavenges reactive oxygen
species (ROS) also conserve the cardioprotective functions of apoA-I, including its ability
to activate lecithin:cholesterol acyltransferase (LCAT), the enzyme that acts on HDLs and
generates almost all of the cholesteryl esters in plasma [101]. However, these agents cannot
reverse the nonenzymatic glycation of apoA-I, or restore LCAT activity once it has been
compromised [101]. Nonenzymatic glycation of lipid-free and lipid-associated apoA-I also
inhibits the anti-inflammatory properties of rHDLs and HDLs from patients with diabetes by
reducing the ability of the particles to inhibit ROS formation in endothelial cells [50,113].
4.2. Oxidative/ER Stress
Oxidative stress leading to the formation of ROS is a hallmark feature of diabetes [114].
The activity of the HDL-associated antioxidant enzyme, PON1, is decreased in HDLs
that contain nonenzymatically glycated apolipoproteins, making the particles less able
to counteract the pro-oxidant environment that characterises the diabetic state [115–117].
Phospholipids and triglycerides are also more readily hydrolysed in HDLs that contain
nonenzymatically glycated apolipoproteins, leading to increased free fatty acid levels and
oxidation that increase the susceptibility of β-cells to failure [115–118].
HDLs that contain nonenzymatically glycated apolipoproteins also have a reduced
capacity to inhibit the oxidation of low density lipoproteins (LDLs) [115,116,119]. As the
accumulation of oxidised LDLs in the artery wall is a key event in atherosclerotic lesion
1Cells 2021, 10, 850 10 of 16
development, it follows that nonenzymatically glycated apoA-I may contribute indirectly
to the accelerated atherosclerotic lesion development that occurs in diabetes [120]. Con-
versely, as oxidised LDLs inhibit insulin gene transcription and promote β-cell apoptosis
in isolated human and rat islets, and in MIN6 and Ins-1E cells, it follows that the capacity
of unmodified HDLs (i.e., those that do not contain nonenzymatically glycated apolipopro-
teins) to conserve β-cell function and insulin content is also related to inhibition of LDL
oxidation [121].
Nonenzymatically glycated HDLs also have reduced sphingosine-1-phosphate (S1P)
levels, a modification that has been implicated directly in accelerated death of rat cardiomy-
ocytes [122]. S1P is a bioactive lipid that, in association with apolipoprotein M, protects
endothelial cells from apoptosis, inflammation and oxidative stress, and reduces the tissue
damage that occurs in the heart following ischemia/reperfusion injury [78,123,124]. The re-
duction of HDL S1P levels in subjects with diabetes has also been implicated as a driver of
impaired endothelial function, and is thus a further cause of the accelerated atherosclerotic
lesion development that prevails in patients with diabetes [125].
4.3. Inflammation
The ability of HDLs to inhibit inflammation in macrophages and endothelial cells,
one of the hallmark cardioprotective functions of these lipoproteins, is compromised in
patients with diabetes. The inability of HDLs isolated from patients with diabetes to reduce
cytokine-activated adhesion molecule expression in endothelial cells has been observed
in large HDLs from patients with T1D even though these particles have elevated S1P and
apoM levels [126]. This somewhat contradictory result has been attributed to a change
in the conformation of apoM that results in an inability of the S1P/apoM complex on
large HDL particles to activate the PI3K/Akt pathway [126]. The selective nonenzymatic
glycation of lysine residues in apoA-I also reduces the ability of the apolipoprotein to inhibit
inflammation in THP-1 macrophages [127]. The mechanistic basis of this observation has
been attributed to an alteration in the conformation of the nonenzymatically glycated
apoA-I that reduces its binding to the macrophage surface [127].
It is noteworthy that the impaired anti-inflammatory effects of HDLs in patients with
diabetes can be restored with a single infusion of unmodified rHDLs that have not been
exposed to a proinflammatory, pro-oxidant environment [128]. In a small study of patients
with T2D that received a single rHDL infusion that transiently increased circulating HDL
levels, the ability of the plasma HDL fraction to inhibit inflammation in the endothelial
cells and the binding of monocytes to fibrinogen both improved, as did the ability of the
patient plasma to efflux cholesterol from macrophages [128].
5. Conclusions
A plethora of preclinical and mechanistic evidence indicating that HDLs have antidia-
betic functions and improve glycaemic control by increasing insulin sensitivity and β-cell
function has emerged in the last decade. The clinical relevance of these studies has been
consolidated by the outcomes of several randomised clinical trials where increasing HDL-C
levels in T2D patients with a CETP inhibitor or with an rHDL infusion is associated with
improved glycaemic control. While these results do not inform on causality, the consistency
of this association is generating significant interest in the development of new therapies for
increasing HDL levels in patients with T2D. The compelling “proof-of-principal” evidence
in support of interventions that increase HDL levels as being beneficial for patients with
T2D that are refractory to currently available antidiabetic agents is compelling. Although it
is not known whether raising HDL levels in patients with T1D would also be beneficial,
this is an area that is definitely worthy of investigation. The challenge going forward
will be how to take advantage of these findings by devising innovative approaches for
developing antidiabetic agents that increase HDL levels or that mimic the antidiabetic
properties of HDLs and their main apolipoproteins.Cells 2021, 10, 850 11 of 16
Author Contributions: B.J.C., K.-L.O., B.M. and K.-A.R. drafted the manuscript and it was edited by
all the authors. All authors have read and agreed to the published version of the manuscript.
Funding: This research was funded by The National Health and Medical Research Council of
Australia grant number APP1148468 and Diabetes Australia grant number Y20G-RYEK.
Acknowledgments: K.-A.R. and B.J.C. are supported by National Health and Medical Research
Council of Australia grants 1148468 and 2004064 and a New South Wales Government Senior
Researcher Grant. K.-L.O. is supported by supported by a National Health and Medical Research
Council of Australia Career Development Fellowship (1122854). B.M. is the recipient of a University
International Postgraduate Award.
Conflicts of Interest: The authors declare no conflict of interest.
References
1. Emerging Risk Factors Collaboration; Di Angelantonio, E.; Sarwar, N.; Perry, P.; Kaptoge, S.; Ray, K.K.; Thompson, A.; Wood,
A.M.; Lewington, S.; Sattar, N. Major lipids, apolipoproteins and risk of vascular disease. JAMA 2009, 302, 1993–2000. [CrossRef]
2. Gordon, T.; Castelli, W.P.; Hjortland, M.C.; Kannel, W.B.; Dawber, T.R. High density lipoprotein as a protective factor against
coronary heart disease. The Framingham Study. Am. J. Med. 1977, 62, 707–714. [CrossRef]
3. Vergeer, M.; Holleboom, A.G.; Kastelein, J.J.; Kuivenhoven, J.A. The HDL hypothesis: Does high-density lipoprotein protect from
atherosclerosis? J. Lipid Res. 2010, 51, 2058–2073. [CrossRef] [PubMed]
4. Morehouse, L.A.; Sugarman, E.D.; Bourassa, P.A.; Sand, T.M.; Zimetti, F.; Gao, F.; Rothblat, G.H.; Milici, A.J. Inhibition of CETP
activity by torcetrapib reduces susceptibility to diet-induced atherosclerosis in New Zealand White rabbits. J. Lipid Res. 2007, 48,
1263–1272. [CrossRef] [PubMed]
5. Lukasova, M.; Malaval, C.; Gille, A.; Kero, J.; Offermanns, S. Nicotinic acid inhibits progression of atherosclerosis in mice through
its receptor GPR109A expressed by immune cells. J. Clin. Investig. 2011, 121, 1163–1173. [CrossRef] [PubMed]
6. Morton, J.; Bao, S.; Vanags, L.Z.; Tsatralis, T.; Ridiandries, A.; Siu, C.W.; Ng, K.M.; Tan, J.T.M.; Celermajer, D.S.; Ng, M.K.C.; et al.
Strikingly different atheroprotective effects of apolipoprotein A-I in early-versus late-stage atherosclerosis. JACC Basic Transl. Sci.
2018, 3, 187–199. [CrossRef]
7. Hps Thrive Collaborative Group; Landray, M.J.; Haynes, R.; Hopewell, J.C.; Parish, S.; Aung, T.; Tomson, J.; Wallendszus, K.;
Craig, M.; Jiang, L.; et al. Effects of extended-release niacin with laropiprant in high-risk patients. N. Engl. J. Med. 2014, 371,
203–212.
8. Nicholls, S.J.; Puri, R.; Ballantyne, C.M.; Jukema, J.W.; Kastelein, J.J.P.; Koenig, W.; Wright, R.S.; Kallend, D.; Wijngaard, P.;
Borgman, M.; et al. Effect of infusion of high-density lipoprotein mimetic containing recombinant apolipoprotein A-I Milano on
coronary disease in patients with an acute coronary syndrome in the MILANO-PILOT Trial: A randomized clinical trial. JAMA
Cardiol. 2018, 3, 806–814. [CrossRef]
9. Nicholls, S.J.; Andrews, J.; Kastelein, J.J.P.; Merkely, B.; Nissen, S.E.; Ray, K.K.; Schwartz, G.G.; Worthley, S.G.; Keyserling, C.;
Dasseux, J.L.; et al. Effect of serial infusions of CER-001, a pre-beta high-density lipoprotein mimetic, on coronary atherosclerosis
in patients following acute coronary syndromes in the CER-001 atherosclerosis regression acute coronary syndrome trial: A
randomized clinical trial. JAMA Cardiol. 2018, 3, 815–822. [PubMed]
10. AIM-HIGH Investigators; Boden, W.E.; Probstfield, J.L.; Anderson, T.; Chaitman, B.R.; Desvignes-Nickens, P.; Koprowicz, K.;
McBride, R.; Teo, K.; Weintraub, W.; et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N.
Engl. J. Med. 2011, 365, 2255–2267. [CrossRef] [PubMed]
11. HPS2-THRIVE Collaborative Group. HPS2-THRIVE randomized placebo-controlled trial in 25 673 high-risk patients of ER
niacin/laropiprant: Trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment. Eur. Heart J.
2013, 34, 1279–1291. [CrossRef] [PubMed]
12. Barter, P.J.; Caulfield, M.; Eriksson, M.; Grundy, S.M.; Kastelein, J.J.; Komajda, M.; Lopez-Sendon, J.; Mosca, L.; Tardif, J.C.; Waters,
D.D.; et al. Illuminate Investigators, Effects of torcetrapib in patients at high risk for coronary events. N. Engl. J. Med. 2007, 357,
2109–2122. [CrossRef] [PubMed]
13. Schwartz, G.G.; Olsson, A.G.; Abt, M.; Ballantyne, C.M.; Barter, P.J.; Brumm, J.; Chaitman, B.R.; Holme, I.M.; Kallend, D.; Leiter,
L.A.; et al. Outcomes Investigators. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N. Engl. J. Med.
2012, 367, 2089–2099. [CrossRef]
14. HPS3/TIMI55–REVEAL Collaborative Group; Bowman, L.; Hopewell, J.C.; Chen, F.; Wallendszus, K.; Stevens, W.; Collins, R.;
Wiviott, S.D.; Cannon, C.P.; Braunwald, E.; et al. Effects of anacetrapib in patients with atherosclerotic vascular disease. N. Engl. J.
Med. 2017, 377, 1217–1227. [CrossRef] [PubMed]
15. Tardif, J.C.; Rheaume, E.; Lemieux Perreault, L.P.; Gregoire, J.C.; Feroz Zada, Y.; Asselin, G.; Provost, S.; Barhdadi, A.; Rhainds, D.;
L’Allier, P.L.; et al. Pharmacogenomic determinants of the cardiovascular effects of dalcetrapib. Circ. Cardiovasc. Genet. 2015, 8,
372–382. [CrossRef]Cells 2021, 10, 850 12 of 16
16. Nissen, S.E.; Pillai, S.G.; Nicholls, S.J.; Wolski, K.; Riesmeyer, J.S.; Weerakkody, G.J.; Foster, W.M.; McErlean, E.; Li, L.; Bhatnagar,
P.; et al. ADCY9 genetic variants and cardiovascular outcomes with evacetrapib in patients with high-risk vascular disease:
A nested case-control study. JAMA Cardiol. 2018, 3, 401–408. [CrossRef]
17. Tardif, J.C.; Dube, M.P.; Pfeffer, M.A.; Waters, D.D.; Koenig, W.; Maggioni, A.P.; McMurray, J.J.V.; Mooser, V.; White, H.D.;
Heinonen, T.; et al. Study design of Dal-GenE, a pharmacogenetic trial targeting reduction of cardiovascular events with
dalcetrapib. Am. Heart J. 2020, 222, 157–165. [CrossRef]
18. Voight, B.F.; Peloso, G.M.; Orho-Melander, M.; Frikke-Schmidt, R.; Barbalic, M.; Jensen, M.K.; Hindy, G.; Holm, H.; Ding, E.L.;
Johnson, T.; et al. Plasma HDL cholesterol and risk of myocardial infarction: A mendelian randomisation study. Lancet 2012, 380,
572–580. [CrossRef]
19. Madsen, C.M.; Varbo, A.; Nordestgaard, B.G. Extreme high high-density lipoprotein cholesterol is paradoxically associated with
high mortality in men and women: Two prospective cohort studies. Eur. Heart J. 2017, 38, 2478–2486. [CrossRef]
20. Zhong, G.C.; Huang, S.Q.; Peng, Y.; Wan, L.; Wu, Y.Q.; Hu, T.Y.; Hu, J.J.; Hao, F.B. HDL-C is associated with mortality from all
causes, cardiovascular disease and cancer in a J-shaped dose-response fashion: A pooled analysis of 37 prospective cohort studies.
Eur. J. Prev. Cardiol. 2020, 27, 1187–1203. [CrossRef]
21. Wang, Y.; Lu, S.; Zhang, G.; Wu, S.; Yan, Y.; Dong, Q.; Liu, B. Anti-inflammatory effects of HDL in mice with rheumatoid arthritis
induced by collagen. Front. Immunol. 2018, 9, 1013. [CrossRef]
22. Cochran, B.J.; Bisoendial, R.J.; Hou, L.; Glaros, E.N.; Rossy, J.; Thomas, S.R.; Barter, P.J.; Rye, K.A. Apolipoprotein A-I increases
insulin secretion and production from pancreatic beta-cells via a G-protein-cAMP-PKA-FoxO1-dependent mechanism. Arter.
Thromb. Vasc. Biol. 2014, 34, 2261–2267. [CrossRef]
23. Fryirs, M.A.; Barter, P.J.; Appavoo, M.; Tuch, B.E.; Tabet, F.; Heather, A.K.; Rye, K.A. Effects of high-density lipoproteins on
pancreatic beta-cell insulin secretion. Arter. Thromb. Vasc. Biol. 2010, 30, 1642–1648. [CrossRef]
24. Hou, L.; Tang, S.; Wu, B.J.; Ong, K.L.; Westerterp, M.; Barter, P.J.; Cochran, B.J.; Tabet, F.; Rye, K.A. Apolipoprotein A-I improves
pancreatic beta-cell function independent of the ATP-binding cassette transporters ABCA1 and ABCG1. FASEB J. 2019, 33,
8479–8489. [CrossRef]
25. Wang, F.; Kohan, A.B.; Kindel, T.L.; Corbin, K.L.; Nunemaker, C.S.; Obici, S.; Woods, S.C.; Davidson, W.S.; Tso, P. Apolipoprotein
A-IV improves glucose homeostasis by enhancing insulin secretion. Proc. Natl. Acad. Sci. USA 2012, 109, 9641–9646. [CrossRef]
26. Stenkula, K.G.; Lindahl, M.; Petrlova, J.; Dalla-Riva, J.; Goransson, O.; Cushman, S.W.; Krupinska, E.; Jones, H.A.; Lagerstedt, J.O.
Single injections of apoA-I acutely improve in vivo glucose tolerance in insulin-resistant mice. Diabetologia 2014, 57, 797–800.
[CrossRef]
27. Domingo-Espin, J.; Lindahl, M.; Nilsson-Wolanin, O.; Cushman, S.W.; Stenkula, K.G.; Lagerstedt, J.O. Dual actions of apolipopro-
tein A-I on glucose-stimulated insulin secretion and insulin-independent peripheral tissue glucose uptake lead to increased heart
and skeletal muscle glucose disposal. Diabetes 2016, 65, 1838–1848. [CrossRef]
28. Tang, S.; Tabet, F.; Cochran, B.J.; Cuesta Torres, L.F.; Wu, B.J.; Barter, P.J.; Rye, K.A. Apolipoprotein A-I enhances insulin-dependent
and insulin-independent glucose uptake by skeletal muscle. Sci. Rep. 2019, 9, 1350. [CrossRef]
29. Pugliese, A. Autoreactive T cells in type 1 diabetes. J. Clin. Investig. 2017, 127, 2881–2891. [CrossRef]
30. Daneman, D. Type 1 diabetes. Lancet 2006, 367, 847–858. [CrossRef]
31. Chatterjee, S.; Khunti, K.; Davies, M.J. Type 2 diabetes. Lancet 2017, 389, 2239–2251. [CrossRef]
32. Zheng, Y.; Ley, S.H.; Hu, F.B. Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nat. Rev.
Endocrinol. 2018, 14, 88–98. [CrossRef]
33. Kahn, S.E.; Hull, R.L.; Utzschneider, K.M. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 2006, 444,
840–846. [CrossRef]
34. Perry, R.J.; Samuel, V.T.; Petersen, K.F.; Shulman, G.I. The role of hepatic lipids in hepatic insulin resistance and type 2 diabetes.
Nature 2014, 510, 84–91. [CrossRef]
35. Prentki, M.; Nolan, C.J. Islet beta cell failure in type 2 diabetes. J. Clin. Investig. 2006, 116, 1802–1812. [CrossRef] [PubMed]
36. Wilson, P.W.; Meigs, J.B.; Sullivan, L.; Fox, C.S.; Nathan, D.M.; D’Agostino, R.B. Prediction of incident diabetes mellitus in
middle-aged adults: The Framingham Offspring Study. Arch. Intern. Med. 2007, 167, 1068–1074. [CrossRef]
37. Schmidt, M.I.; Duncan, B.B.; Bang, H.; Pankow, J.S.; Ballantyne, C.M.; Golden, S.H.; Folsom, A.R.; Chambless, L.E.; Atherosclerosis
Risk in Communities Investigators. Identifying individuals at high risk for diabetes: The Atherosclerosis Risk in Communities
study. Diabetes Care 2005, 28, 2013–2018. [CrossRef]
38. Abbasi, A.; Corpeleijn, E.; Gansevoort, R.T.; Gans, R.O.; Hillege, H.L.; Stolk, R.P.; Navis, G.; Bakker, S.J.; Dullaart, R.P. Role of
HDL cholesterol and estimates of HDL particle composition in future development of type 2 diabetes in the general population:
The PREVEND study. J. Clin. Endocrinol. Metab. 2013, 98, E1352–E1359. [CrossRef]
39. Lee, S.H.; Kim, H.S.; Park, Y.M.; Kwon, H.S.; Yoon, K.H.; Han, K.; Kim, M.K. HDL-cholesterol, its variability, and the risk of
diabetes: A nationwide population-based study. J. Clin. Endocrinol. Metab. 2019, 104, 5633–5641. [CrossRef]
40. Hwang, Y.C.; Ahn, H.Y.; Park, S.W.; Park, C.Y. Association of HDL-C and apolipoprotein A-I with the risk of type 2 diabetes in
subjects with impaired fasting glucose. Eur. J. Endocrinol. 2014, 171, 137–142. [CrossRef]
41. Hermans, M.P.; Amoussou-Guenou, K.D.; Bouenizabila, E.; Sadikot, S.S.; Ahn, S.A.; Rousseau, M.F. Size, density and cholesterol
load of HDL predict microangiopathy, coronary artery disease and beta-cell function in men with T2DM. Diabetes Metab. Syndr.
2017, 11, 125–131. [CrossRef]Cells 2021, 10, 850 13 of 16
42. Mazer, N.A.; Giulianini, F.; Paynter, N.P.; Jordan, P.; Mora, S. A comparison of the theoretical relationship between HDL size and
the ratio of HDL cholesterol to apolipoprotein A-I with experimental results from the Women’s Health Study. Clin. Chem. 2013,
59, 949–958. [CrossRef]
43. Morton, A.M.; Koch, M.; Mendivil, C.O.; Furtado, J.D.; Tjonneland, A.; Overvad, K.; Wang, L.; Jensen, M.K.; Sacks, F.M.
Apolipoproteins E and CIII interact to regulate HDL metabolism and coronary heart disease risk. JCI Insight 2018, 3, 3. [CrossRef]
44. Jensen, M.K.; Aroner, S.A.; Mukamal, K.J.; Furtado, J.D.; Post, W.S.; Tsai, M.Y.; Tjonneland, A.; Polak, J.F.; Rimm, E.B.; Overvad,
K.; et al. High-density lipoprotein subspecies defined by presence of apolipoprotein C-III and incident coronary heart disease in
four cohorts. Circulation 2018, 137, 1364–1373. [CrossRef]
45. Cheung, M.C.; Albers, J.J. Characterization of lipoprotein particles isolated by immunoaffinity chromatography. Particles
containing A-I and A-II and particles containing A-I but no A-II. J. Biol. Chem. 1984, 259, 12201–12209. [CrossRef]
46. Asztalos, B.F.; Schaefer, E.J.; Horvath, K.V.; Yamashita, S.; Miller, M.; Franceschini, G.; Calabresi, L. Role of LCAT in HDL
remodeling: Investigation of LCAT deficiency states. J. Lipid Res. 2007, 48, 592–599. [CrossRef]
47. Vaisar, T.; Kanter, J.E.; Wimberger, J.; Irwin, A.D.; Gauthier, J.; Wolfson, E.; Bahnam, V.; Wu, I.H.; Shah, H.; Keenan, H.A.; et al.
High concentration of medium-sized HDL particles and enrichment in HDL paraoxonase 1 associate with protection from
vascular complications in people with long-standing type 1 diabetes. Diabetes Care 2020, 43, 178–186. [CrossRef]
48. Ahmed, M.O.; Byrne, R.E.; Pazderska, A.; Segurado, R.; Guo, W.; Gunness, A.; Frizelle, I.; Sherlock, M.; Ahmed, K.S.; McGowan,
A.; et al. HDL particle size is increased and HDL-cholesterol efflux is enhanced in type 1 diabetes: A cross-sectional study.
Diabetologia 2021, 64, 656–667. [CrossRef]
49. Mooradian, A.D. Dyslipidemia in type 2 diabetes mellitus. Nat. Clin. Pract. Endocrinol. Metab. 2009, 5, 150–159. [CrossRef]
50. Nobecourt, E.; Tabet, F.; Lambert, G.; Puranik, R.; Bao, S.; Yan, L.; Davies, M.J.; Brown, B.E.; Jenkins, A.J.; Dusting, G.J.; et al.
Nonenzymatic glycation impairs the antiinflammatory properties of apolipoprotein A-I. Arter. Thromb. Vasc. Biol. 2010, 30,
766–772. [CrossRef]
51. Colhoun, H.M.; Otvos, J.D.; Rubens, M.B.; Taskinen, M.R.; Underwood, S.R.; Fuller, J.H. Lipoprotein subclasses and particle sizes
and their relationship with coronary artery calcification in men and women with and without type 1 diabetes. Diabetes 2002, 51,
1949–1956. [CrossRef] [PubMed]
52. Gourgari, E.; Ma, J.; Playford, M.P.; Mehta, N.N.; Goldman, R.; Remaley, A.T.; Gordon, S.M. Proteomic alterations of HDL in
youth with type 1 diabetes and their associations with glycemic control: A case-control study. Cardiovasc. Diabetol. 2019, 18, 43.
[CrossRef] [PubMed]
53. Medina-Bravo, P.; Medina-Urrutia, A.; Juarez-Rojas, J.G.; Cardoso-Saldana, G.; Jorge-Galarza, E.; Posadas-Sanchez, R.; Coyote-
Estrada, N.; Nishimura-Meguro, E.; Posadas-Romero, C. Glycemic control and high-density lipoprotein characteristics in
adolescents with type 1 diabetes. Pediatr. Diabetes 2013, 14, 399–406. [CrossRef] [PubMed]
54. Garvey, W.T.; Kwon, S.; Zheng, D.; Shaughnessy, S.; Wallace, P.; Hutto, A.; Pugh, K.; Jenkins, A.J.; Klein, R.L.; Liao, Y. Effects of
insulin resistance and type 2 diabetes on lipoprotein subclass particle size and concentration determined by nuclear magnetic
resonance. Diabetes 2003, 52, 453–462. [CrossRef]
55. Mora, S.; Otvos, J.D.; Rosenson, R.S.; Pradhan, A.; Buring, J.E.; Ridker, P.M. Lipoprotein particle size and concentration by nuclear
magnetic resonance and incident type 2 diabetes in women. Diabetes 2010, 59, 1153–1160. [CrossRef]
56. Tabara, Y.; Arai, H.; Hirao, Y.; Takahashi, Y.; Setoh, K.; Kawaguchi, T.; Kosugi, S.; Ito, Y.; Nakayama, T.; Matsuda, F.; et al. Different
inverse association of large high-density lipoprotein subclasses with exacerbation of insulin resistance and incidence of type 2
diabetes: The Nagahama study. Diabetes Res. Clin. Pract. 2017, 127, 123–131. [CrossRef]
57. Wu, X.; Yu, Z.; Su, W.; Isquith, D.A.; Neradilek, M.B.; Lu, N.; Gu, F.; Li, H.; Zhao, X.Q. Low levels of ApoA1 improve risk
prediction of type 2 diabetes mellitus. J. Clin. Lipidol. 2017, 11, 362–368. [CrossRef]
58. Mackey, R.H.; Mora, S.; Bertoni, A.G.; Wassel, C.L.; Carnethon, M.R.; Sibley, C.T.; Goff, D.C., Jr. Lipoprotein particles and incident
type 2 diabetes in the multi-ethnic study of atherosclerosis. Diabetes Care 2015, 38, 628–636. [CrossRef]
59. Hwang, Y.C.; Hayashi, T.; Fujimoto, W.Y.; Kahn, S.E.; Leonetti, D.L.; McNeely, M.J.; Boyko, E.J. Differential association between
HDL subclasses and the development of type 2 diabetes in a prospective study of Japanese Americans. Diabetes Care 2015, 38,
2100–2105. [CrossRef]
60. Despres, J.P.; Lemieux, I.; Bergeron, J.; Pibarot, P.; Mathieu, P.; Larose, E.; Rodes-Cabau, J.; Bertrand, O.F.; Poirier, P. Abdominal
obesity and the metabolic syndrome: Contribution to global cardiometabolic risk. Arter. Thromb. Vasc. Biol. 2008, 28, 1039–1049.
[CrossRef]
61. Haase, C.L.; Tybjaerg-Hansen, A.; Nordestgaard, B.G.; Frikke-Schmidt, R. HDL cholesterol and risk of type 2 diabetes:
A Mendelian Randomization study. Diabetes 2015, 64, 3328–3333. [CrossRef]
62. Drew, B.G.; Duffy, S.J.; Formosa, M.F.; Natoli, A.K.; Henstridge, D.C.; Penfold, S.A.; Thomas, W.G.; Mukhamedova, N.; de
Courten, B.; Forbes, J.M.; et al. High-density lipoprotein modulates glucose metabolism in patients with type 2 diabetes mellitus.
Circulation 2009, 119, 2103–2111. [CrossRef]
63. Menon, V.; Kumar, A.; Patel, D.R.; St John, J.; Riesmeyer, J.; Weerakkody, G.; Ruotolo, G.; Wolski, K.E.; McErlean, E.; Cremer,
P.C.; et al. Effect of CETP inhibition with evacetrapib in patients with diabetes mellitus enrolled in the ACCELERATE trial. BMJ
Open Diabetes Res. Care 2020, 8, e000943. [CrossRef]You can also read
